tbuckley/cabot-search huggingface dataset:
Advances in Trop2-targeted therapy: Novel agents and opportunities beyond breast cancer
Authors: Xinlin Liu, Junwen Deng, Yang Yuan, Wujun Chen, Wenshe Sun, Yanhong Wang, Haiming Huang, Bing Liang, Tao Ming, Jialian Wen, Binghuan Huang, Dongming Xing
Journal: Pharmacology & Therapeutics (2022)

Trop2 is a transmembrane glycoprotein and calcium signal transducer with limited expression in normal human tissues. It is consistently overexpressed in a variety of malignant tumors and participates in several oncogenic signaling pathways that lead to tumor development, invasion, and metastasis. As a result, Trop2 has become an attractive therapeutic target in cancer treatment. The anti-Trop2 antibody-drug conjugate (Trodelvy™, sacituzumab govitecan) has been approved to treat metastatic triple-negative breast cancer. However, it is still unclear whether the success observed in Trop2-positive breast cancer could be replicated in other tumor types, owing to the differences in the expression levels and functions of Trop2 across cancer types. In this review, we summarize the recent progress on the structures and functions of Trop2 and highlight the potential diagnostic and therapeutic value of Trop2 beyond breast cancer. In addition, the promising novel Trop2-targeted agents in the clinic were discussed, which will likely alter the therapeutic landscape of Trop2-positive tumors in the future.
Bidirectional prediction of facial and bony shapes for orthognathic surgical planning
Authors: Lei Ma, Chunfeng Lian, Daeseung Kim, Deqiang Xiao, Dongming Wei, Qin Liu, Tianshu Kuang, Maryam Ghanbari, Guoshi Li, Jaime Gateno, Steve G.F. Shen, Li Wang, Dinggang Shen, James J. Xia, Pew-Thian Yap
Journal: Medical Image Analysis (2022)
Metabolic modulation of synaptic failure and thalamocortical hypersynchronization with preserved consciousness in Glut1 deficiency
Authors: Karthik Rajasekaran, Qian Ma, Levi B. Good, Gauri Kathote, Vikram Jakkamsetti, Peiying Liu, Adrian Avila, Sharon Primeaux, Julio Enciso Alva, Kia H. Markussen, Isaac Marin-Valencia, Deepa Sirsi, Peter M. S. Hacker, Matthew S. Gentry, Jianzhong Su, Hanzhang Lu, Juan M. Pascual
Journal: Science Translational Medicine (2022)

Individuals with glucose transporter type I deficiency (G1D) habitually experience nutrient-responsive epilepsy associated with decreased brain glucose. However, the mechanistic association between blood glucose concentration and brain excitability in the context of G1D remains to be elucidated. Electroencephalography (EEG) in G1D individuals revealed nutrition time-dependent seizure oscillations often associated with preserved volition despite electrographic generalization and uniform average oscillation duration and periodicity, suggesting increased facilitation of an underlying neural loop circuit. Nonlinear EEG ictal source localization analysis and simultaneous EEG/functional magnetic resonance imaging converged on the thalamus-sensorimotor cortex as one potential circuit, and 18 F-deoxyglucose positron emission tomography ( 18 F-DG-PET) illustrated decreased glucose accumulation in this circuit. This pattern, reflected in a decreased thalamic to striatal 18 F signal ratio, can aid with the PET imaging diagnosis of the disorder, whereas the absence of noticeable ictal behavioral changes challenges the postulated requirement for normal thalamocortical activity during consciousness. In G1D mice, 18 F-DG-PET and mass spectrometry also revealed decreased brain glucose and glycogen, but preserved tricarboxylic acid cycle intermediates, indicating no overall energy metabolism failure. In brain slices from these animals, synaptic inhibition of cortical pyramidal neurons and thalamic relay neurons was decreased, and neuronal disinhibition was mitigated by metabolic sources of carbon; tonic-clonic seizures were also suppressed by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor inhibition. These results pose G1D as a thalamocortical synaptic disinhibition disease associated with increased glucose-dependent neuronal excitability, possibly in relation to reduced glycogen. Together with findings in other metabolic defects, inhibitory neuron dysfunction is emerging as a modulable mechanism of hyperexcitability.
<i>NOS1</i> mutations cause hypogonadotropic hypogonadism with sensory and cognitive deficits that can be reversed in infantile mice
Authors: Konstantina Chachlaki, Andrea Messina, Virginia Delli, Valerie Leysen, Csilla Maurnyi, Chieko Huber, Gaëtan Ternier, Katalin Skrapits, Georgios Papadakis, Sonal Shruti, Maria Kapanidou, Xu Cheng, James Acierno, Jesse Rademaker, Sowmyalakshmi Rasika, Richard Quinton, Marek Niedziela, Dagmar L’Allemand, Duarte Pignatelli, Mirjam Dirlewander, Mariarosaria Lang-Muritano, Patrick Kempf, Sophie Catteau-Jonard, Nicolas J. Niederländer, Philippe Ciofi, Manuel Tena-Sempere, John Garthwaite, Laurent Storme, Paul Avan, Erik Hrabovszky, Alan Carleton, Federico Santoni, Paolo Giacobini, Nelly Pitteloud, Vincent Prevot
Journal: Science Translational Medicine (2022)

The nitric oxide (NO) signaling pathway in hypothalamic neurons plays a key role in the regulation of the secretion of gonadotropin-releasing hormone (GnRH), which is crucial for reproduction. We hypothesized that a disruption of neuronal NO synthase (NOS1) activity underlies some forms of hypogonadotropic hypogonadism. Whole-exome sequencing was performed on a cohort of 341 probands with congenital hypogonadotropic hypogonadism to identify ultrarare variants in NOS1 . The activity of the identified NOS1 mutant proteins was assessed by their ability to promote nitrite and cGMP production in vitro. In addition, physiological and pharmacological characterization was carried out in a Nos1 -deficient mouse model. We identified five heterozygous NOS1 loss-of-function mutations in six probands with congenital hypogonadotropic hypogonadism (2%), who displayed additional phenotypes including anosmia, hearing loss, and intellectual disability. NOS1 was found to be transiently expressed by GnRH neurons in the nose of both humans and mice, and Nos1 deficiency in mice resulted in dose-dependent defects in sexual maturation as well as in olfaction, hearing, and cognition. The pharmacological inhibition of NO production in postnatal mice revealed a critical time window during which Nos1 activity shaped minipuberty and sexual maturation. Inhaled NO treatment at minipuberty rescued both reproductive and behavioral phenotypes in Nos1 -deficient mice. In summary, lack of NOS1 activity led to GnRH deficiency associated with sensory and intellectual comorbidities in humans and mice. NO treatment during minipuberty reversed deficits in sexual maturation, olfaction, and cognition in Nos1 mutant mice, suggesting a potential therapy for humans with NO deficiency.
A germline SNP in BRMS1 predisposes patients with lung adenocarcinoma to metastasis and can be ameliorated by targeting c-fos
Authors: Yuan Liu, Neel Chudgar, Brooke Mastrogiacomo, Di He, Manendra B. Lankadasari, Samhita Bapat, Gregory D. Jones, Francisco Sanchez-Vega, Kay See Tan, Nikolaus Schultz, Semanti Mukherjee, Kenneth Offit, Yongde Bao, Matthew J. Bott, Natasha Rekhtman, Prasad S. Adusumilli, Bob T. Li, Marty W. Mayo, David R. Jones
Journal: Science Translational Medicine (2022)

About 50% of patients with early-stage, surgically resected lung cancer will develop distant metastasis. There remains an unmet need to identify patients likely to develop recurrence and to design innovative therapies to decrease this risk. Two primary isoforms of BRMS1, v1 and v2, are present in humans. Using next-generation sequencing of BRMS1 on matched human noncancerous lung tissue and non–small cell lung cancer (NSCLC) specimens, we identified single-nucleotide polymorphism (SNP) rs1052566 that results in an A273V mutation of BRMS1v2. This SNP is homozygous ( BRMS1v2 A273V/A273V ) in 8% of the population and correlates with aggressive biology in lung adenocarcinoma (LUAD). Mechanistically, we show that BRMS1v2 A273V abolishes the metastasis suppressor function of BRMS1v2 and promotes robust cell invasion and metastases by activation of c-fos–mediated gene-specific transcriptional regulation. BRMS1v2 A273V increases cell invasion in vitro and increases metastases in both tail-vein injection xenografts and LUAD patient-derived organoid (PDO) intracardiac injection metastasis in vivo models. Moreover, we show that BRMS1v2 A273V fails to interact with nuclear Src, thereby activating intratumoral c-fos in vitro. Higher c-fos results in up-regulation of CEACAM6 , which drives metastases in vitro and in vivo. Using both xenograft and PDO metastasis models, we repurposed T5224 for treatment, a c-fos pharmacologic inhibitor investigated in clinical trials for arthritis, and observed suppression of metastases in BRMS1v2 A273V/A273V LUAD in mice. Collectively, we elucidate the mechanism of BRMS1v2 A273V/A273V -induced metastases and offer a putative therapeutic strategy for patients with LUAD who have this germline alteration.
Assessment of cholesterol homeostasis in the living human brain
Authors: Ahmed Haider, Chunyu Zhao, Lu Wang, Zhiwei Xiao, Jian Rong, Xiaotian Xia, Zhen Chen, Stefanie K. Pfister, Natalia Mast, Eylan Yutuc, Jiahui Chen, Yinlong Li, Tuo Shao, Geoffrey I. Warnock, Alyaa Dawoud, Theresa R. Connors, Derek H. Oakley, Huiyi Wei, Jinghao Wang, Zhihua Zheng, Hao Xu, April T. Davenport, James B. Daunais, Richard S. Van, Yihan Shao, Yuqin Wang, Ming-Rong Zhang, Catherine Gebhard, Irina Pikuleva, Allan I. Levey, William J. Griffiths, Steven H. Liang
Journal: Science Translational Medicine (2022)

Alterations in brain cholesterol homeostasis have been broadly implicated in neurological disorders. Notwithstanding the complexity by which cholesterol biology is governed in the mammalian brain, excess neuronal cholesterol is primarily eliminated by metabolic clearance via cytochrome P450 46A1 (CYP46A1). No methods are currently available for visualizing cholesterol metabolism in the living human brain; therefore, a noninvasive technology that quantitatively measures the extent of brain cholesterol metabolism via CYP46A1 could broadly affect disease diagnosis and treatment options using targeted therapies. Here, we describe the development and testing of a CYP46A1-targeted positron emission tomography (PET) tracer, 18 F-CHL-2205 ( 18 F-Cholestify). Our data show that PET imaging readouts correlate with CYP46A1 protein expression and with the extent to which cholesterol is metabolized in the brain, as assessed by cross-species postmortem analyses of specimens from rodents, nonhuman primates, and humans. Proof of concept of in vivo efficacy is provided in the well-established 3xTg-AD murine model of Alzheimer’s disease (AD), where we show that the probe is sensitive to differences in brain cholesterol metabolism between 3xTg-AD mice and control animals. Furthermore, our clinical observations point toward a considerably higher baseline brain cholesterol clearance via CYP46A1 in women, as compared to age-matched men. These findings illustrate the vast potential of assessing brain cholesterol metabolism using PET and establish PET as a sensitive tool for noninvasive assessment of brain cholesterol homeostasis in the clinic.
Pancreatic islet-specific engineered T <sub>regs</sub> exhibit robust antigen-specific and bystander immune suppression in type 1 diabetes models
Authors: Soo Jung Yang, Akhilesh K. Singh, Travis Drow, Tori Tappen, Yuchi Honaker, Fariba Barahmand-pour-Whitman, Peter S. Linsley, Karen Cerosaletti, Kelsey Mauk, Yufei Xiang, Jessica Smith, Emma Mortensen, Peter J. Cook, Karen Sommer, Iram Khan, Denny Liggitt, David J. Rawlings, Jane H. Buckner
Journal: Science Translational Medicine (2022)

Adoptive transfer of regulatory T cells (Tregs) is therapeutic in type 1 diabetes (T1D) mouse models. Tregs that are specific for pancreatic islets are more potent than polyclonal Tregs in preventing disease. However, the frequency of antigen-specific natural Tregs is extremely low, and ex vivo expansion may destabilize Tregs, leading to an effector phenotype. Here, we generated durable, antigen-specific engineered Tregs (EngTregs) from primary human CD4+ T cells by combining FOXP3 homology-directed repair editing and lentiviral T cell receptor (TCR) delivery. Using TCRs derived from clonally expanded CD4+ T cells isolated from patients with T1D, we generated islet-specific EngTregs that suppressed effector T cell (Teff) proliferation and cytokine production. EngTregs suppressed Teffs recognizing the same islet antigen in addition to bystander Teffs recognizing other islet antigens through production of soluble mediators and both direct and indirect mechanisms. Adoptively transferred murine islet-specific EngTregs homed to the pancreas and blocked diabetes triggered by islet-specific Teffs or diabetogenic polyclonal Teffs in recipient mice. These data demonstrate the potential of antigen-specific EngTregs as a targeted therapy for preventing T1D.
Role of serum‐free light chain assay for defining response and progression in immunoglobulin secretory multiple myeloma
Authors: Paola Tacchetti, Serena Rocchi, Elena Zamagni, Simona Barbato, Ilaria Rizzello, Gabriella De Cicco, Lucia Pantani, Katia Mancuso, Alessio Fusco, Luca Dozza, Margherita Ursi, Emanuele Favero, Carolina Terragna, Nicoletta Testoni, Michele Cavo
Journal: American Journal of Hematology (2022)

The International Myeloma Working Group (IMWG) guidelines recommend using electrophoresis and immunofixation to define response and progressive disease (PD) in immunoglobulin (Ig) secretory multiple myeloma (Ig-MM), whereas the role of serum-free light chain (sFLC) is controversial. We retrospectively analyzed the value of adding sFLC assays in the definition of response and PD according to IMWG criteria in 339 Ig-MM patients treated with a first-line novel agent-based therapy (median follow-up 54 months). sFLC PD was defined according to conventional criteria plus increased sFLC levels, or sFLC escape (sFLCe); progression/sFLCe-free survival (ePFS) was the time from the start of treatment to the date of first PD or sFLCe, or death; overall survival after PD/sFLCe (OS after Pe) was the time from first PD or sFLCe to the date of death. 148 (44%) patients achieved a complete response and 198 (60%) a normal sFLC ratio (sFLCR). sFLCR normalization was an independent prognostic factor for extended PFS (HR = 0.46, p = 0.001) and OS (HR = 0.47, p = 0.006) by multivariable analysis. 175 (52%) patients experienced PD according to the IMWG criteria, whereas 180 (53%) experienced PD or sFLCe. Overall, a sFLCe was observed in 31 (9%) patients. Median PFS and ePFS were both equal to 36 (95% CI = 32-42, and 32-40, respectively) months. sFLC PD adversely affected the OS after Pe compared to PD with increasing monoclonal Ig only (HR = 0.52, p = 0.012). Our results support the inclusion of the sFLC assay for defining response and PD in Ig-MM.
Acute hypoxaemic respiratory failure after treatment with lower tidal volume ventilation facilitated by extracorporeal carbon dioxide removal: long-term outcomes from the REST randomised trial
Authors: Andrew J Boyle, Clíona McDowell, Ashley Agus, Danielle Logan, Jonathan D Stewart, Colette Jackson, Jeanette Mills, James J McNamee, Daniel F McAuley
Journal: Thorax (2022)

Introduction Lower tidal volume ventilation, facilitated by veno-venous extracorporeal carbon dioxide removal (vv-ECCO 2 R), does not improve 90-day mortality in patients with acute hypoxaemic respiratory failure (AHRF). The aim of this analysis was to evaluate the effect of this therapeutic strategy on long-term outcomes. Methods This was a prespecified analysis of the REST trial, a UK-wide multicentre randomised clinical trial that compared lower tidal volume ventilation, facilitated by vv-ECCO 2 R (intervention), with standard care in the treatment of patients with moderate-to-severe AHRF. Mortality to 2 years was assessed, while respiratory function, post-traumatic stress disorder, cognitive function and health-related quality of life were evaluated in survivors at 1 year using standardised questionnaires. Results Of 412 patients enrolled into the REST trial, 391 (95%) had 2-year mortality outcome data available. There was no difference in the time to death between intervention and standard care (HR 1.08 (0.81, 1.44); log-rank test p=0.61). 161 patients alive at 1 year provided at least one questionnaire response. There was no difference in respiratory function, post-traumatic stress disorder, cognitive dysfunction or health-related quality of life between patients allocated to intervention or standard care. Conclusion Lower-tidal volume ventilation facilitated by vv-ECCO 2 R does not affect 1-year mortality in patients with moderate-to-severe AHRF. Of the patients who provided questionnaire responses, there was no treatment effect on long-term respiratory function, post-traumatic stress disorder, cognitive dysfunction or health-related quality of life. Trial registration number ClinicalTrials.gov identifier: NCT02654327 .
Signaling pathways in the regulation of cancer stem cells and associated targeted therapy
Authors: Wang Manni, Wu Min
Journal: MedComm (2022)

Cancer stem cells (CSCs) are defined as a subpopulation of malignant tumor cells with selective capacities for tumor initiation, self-renewal, metastasis, and unlimited growth into bulks, which are believed as a major cause of progressive tumor phenotypes, including recurrence, metastasis, and treatment failure. A number of signaling pathways are involved in the maintenance of stem cell properties and survival of CSCs, including well-established intrinsic pathways, such as the Notch, Wnt, and Hedgehog signaling, and extrinsic pathways, such as the vascular microenvironment and tumor-associated immune cells. There is also intricate crosstalk between these signal cascades and other oncogenic pathways. Thus, targeting pathway molecules that regulate CSCs provides a new option for the treatment of therapy-resistant or -refractory tumors. These treatments include small molecule inhibitors, monoclonal antibodies that target key signaling in CSCs, as well as CSC-directed immunotherapies that harness the immune systems to target CSCs. This review aims to provide an overview of the regulating networks and their immune interactions involved in CSC development. We also address the update on the development of CSC-directed therapeutics, with a special focus on those with application approval or under clinical evaluation.
Pharmacy services at the Tokyo 2020 Olympic and Paralympic Games: perspectives of the pharmacy workforce
Authors: Kumiko Kasashi, Ayaka Sato, Mark Stuart, Trudy Thomas, Sung Hwa Kim, Da Mi Jang, Hayley File, Satomi Suzuki, Sandy Jeong Rhie
Journal: British Journal of Sports Medicine (2022)

To evaluate the awareness of the volunteer pharmacy workforce of medication use and their satisfaction with the pharmacy services of the Tokyo 2020 Olympic and Paralympic Games from a pharmacist's perspective.A questionnaire was developed from related articles in published peer-reviewed journals and modified prior to distribution to the whole population of pharmacists serving at the Tokyo 2020 Olympic and Paralympic Games. Validity tests were conducted based on expert opinions and Cronbach's alpha (0.79). The questionnaire consisted of demographics (11 questions), knowledge of medication use in sports (8 questions) and satisfaction on the provision of the service (5 questions). Responses using a 5-point-Likert scale, from strongly agree (5) to strongly disagree (1), and two free text questions were analysed with descriptive statistics.The response rate was 86% (n=32/37). Overall, the pharmacists reported a high awareness of medication use. Specifically, questions on the prohibited list of medications (mean 4.0±SD 0.7), COVID-19 policy (3.8±0.9), use of alternative non-prohibited medications (3.6±1.0) and therapeutic use exemptions (3.5±0.9). Moreover, they rated high satisfaction with the pharmacy service they provided. However, rates were ≤3 for knowledge of the International Olympic Committee Needle Policy (2.6±1.0), Medication Importation Declaration (2.9±1.0) and communication skills (3.0±1.0).Pharmacists were confident and satisfied with the pharmacy service at the games. The study confirms the importance of prior training and education. Game-specific policies and strategies to improve communication skills should be included in the pharmacy education for future Games.
Belimumab use during pregnancy: a summary of birth defects and pregnancy loss from belimumab clinical trials, a pregnancy registry and postmarketing reports
Authors: Michelle Petri, Helain Landy, Megan E B Clowse, Kim Gemzoe, Munther Khamashta, Milena Kurtinecz, Roger A Levy, Andrew Liu, Rebecca Marino, Paige Meizlik, Jeanne M Pimenta, Kelsey Sumner, Hugh Tilson, Mary Beth Connolly, Keele Wurst, Julia Harris, Holly Quasny, Patricia Juliao, David A Roth
Journal: Annals of the Rheumatic Diseases (2022)

Describe available data on birth defects and pregnancy loss in women with systemic lupus erythematosus (SLE) exposed to belimumab.
PU.1 promotes development of rheumatoid arthritis via repressing FLT3 in macrophages and fibroblast-like synoviocytes
Authors: Jiajie Tu, Weile Chen, Yilong Fang, Dafei Han, Yizhao Chen, Haifeng Jiang, Xuewen Tan, Zhen Xu, Xuming Wu, Huihui Wang, Xiangling Zhu, Wenming Hong, Zhenbao Li, Chen Zhu, Xinming Wang, Wei Wei
Journal: Annals of the Rheumatic Diseases (2022)

To uncover the function and underlying mechanism of an essential transcriptional factor, PU.1, in the development of rheumatoid arthritis (RA).The expression and localisation of PU.1 and its potential target, FMS-like tyrosine kinase 3 (FLT3), in the synovium of patients with RA were determined by western blot and immunohistochemical (IHC) staining. UREΔ (with PU.1 knockdown) and FLT3-ITD (with FLT3 activation) mice were used to establish collagen antibody-induced arthritis (CAIA). For the in vitro study, the effects of PU.1 and FLT3 on primary macrophages and fibroblast-like synoviocytes (FLS) were investigated using siRNAs. Mechanistically, luciferase reporter assays, western blotting, FACS and IHC were conducted to show the direct regulation of PU.1 on the transcription of FLT3 in macrophages and FLS. Finally, a small molecular inhibitor of PU.1, DB2313, was used to further illustrate the therapeutic effects of DB2313 on arthritis using two in vivo models, CAIA and collagen-induced arthritis (CIA).The expression of PU.1 was induced in the synovium of patients with RA when compared with that in osteoarthritis patients and normal controls. FLT3 and p-FLT3 showed opposite expression patterns compared with PU.1 in RA. The CAIA model showed that PU.1 was an activator, whereas FLT3 was a repressor, of the development of arthritis in vivo. Moreover, results from in vitro assays were consistent with the in vivo results: PU.1 promoted hyperactivation and inflammatory status of macrophages and FLS, whereas FLT3 had the opposite effects. In addition, PU.1 inhibited the transcription of FLT3 by directly binding to its promoter region. The PU.1 inhibitor DB2313 clearly alleviated the effects on arthritis development in the CAIA and CIA models.These results support the role of PU.1 in RA and may have therapeutic implications by directly repressing FLT3. Therefore, targeting PU.1 might be a potential therapeutic approach for RA.